It runs north from Ross-on-Wye in Herefordshire via Hereford, Leominster, Ludlow, Shrewsbury and Whitchurch, then continues through central Cheshire to Warrington and Wigan before terminating at its junction with the A6 road just south of Bamber Bridge, near the junction of the M6, M65 and M61 motorways.

As is hinted at by the way the place name of Stretton recurs along its route, its central part follows Iter XII of the Roman Antonine Itinerary.

[1] The stretch between Ross-on-Wye and the A5 at Shrewsbury is a trunk road, maintained by National Highways.

[2] From the A6 at Bamber Bridge, south of Preston, the road runs parallel to the M6 motorway, through Leyland towards Wigan.

It passes over a roundabout with the A5061 situated on the River Mersey, then goes past Priestley College.

The road passes over the West Coast Main Line railway after the Weaverham Roundabout.

It then crosses the A54 near Abbots Moss Hall, and the road passes through Cotebrook, near Little Budworth Country Park.

The road travels over the Shropshire Union Canal and under the Welsh Marches Line railway (to Hereford) south of Tiverton.

It passes near Sir John Talbot's Technology College (on the A525), then crosses over the railway and also overlaps the A525 (Newcastle-under-Lyme to Rhyl).

At the end of the bypass, the road overlaps as a dual-carriageway for 2+1⁄2 miles (4.0 km) with the A41, then leaves the A41 at a roundabout near Prees Heath, near the former RAF Tilstock airfield.

The bypass travels over the River Severn and under the railway and overlaps the A5 from the Preston Island roundabout.

The route leaves the A5 at the Bayston Hill Roundabout on the south of the bypass, with the A5112 heading into Shrewsbury.

It passes near Lyth Hill Country Park, following the Welsh Marches Line (until Woofferton).

It crosses the Cound Brook near the Bridge Innbefore passing through Dorrington, with The Horseshoes and over the railway.

At Craven Arms, there is the Shropshire Hills Discovery Centre, and it meets the east-west B4368.

South of Ashton the road passes through the Capability Brown parkland of Berrington Hall.

At the southern end of the Leominster Bypass the A49 passes the Cadbury's Marlbrook chocolate factory.

The road passes right through the city centre, causing serious congestion on both the north and south sides of the River Wye.